Breast cancer is the most common malignancy among women and along with lung cancer has the highest fatality rate of all cancers affecting women. The search for new active agents and strategies to improve the prognosis for patients with metastatic breast cancer continues. In spite of the existence of numerous chemotherapeutic agents and regimens found to have antitumor activity, research continues in an effort to find improved treatment modalities, since survival rates in certain cancers remain low. For example, less than one in five patients with Stage IV (advanced) breast cancer survives more than five years after distant metastases are detected.
Methotrexate has been one of the standard anti-tumor agents in the treatment of breast cancer. Edatrexate (10-ethyl-10-deaza-aminopterin) is a relatively new structural analog of methotrexate which was developed at the Memorial Sloan-Kettering Cancer Center in New York in collaboration with SRI International. Like methotrexate, edatrexate inhibits dihydrofolate reductase. However, edatrexate is deemed a promising alternative because in preclinical tests it proved to have a greater antitumor activity than methotrexate against a number of tumors, partly attributed to the fact that this new analog accumulated in sensitive tumor cells to a greater extent than its predecessor methotrexate and was more selectively retained by the tumor cells. See, e.g. Kris et al., Cancer Research 48:5573-5579 (1988) and Sirotnak et al., NCI Monographs, No. 5 (1987).
The use of edatrexate as a single agent treatment against various tumors has met with some success. Studies of non-small cell lung cancer patients have reported positive results, with response rates being in the range of 30%. Grant et al., Cancer Investigation 11:36-45 (1993). Antitumor activity of edatrexate has also been observed in patients with non-Hodgkin's lymphoma, head and neck carcinoma, and breast cancer. (Vandenberg et al., Proc. Am. Soc. Clin. Oncol. 11:51 (1992); Schornagel et al., Ann. of Oncology 3:549-552 (1992). No anti-tumor activity was observed in patients with smallcell lung cancer or metastatic colorectal carcinoma. See Grant et al., supra, for a general review of clinical trials with edatrexate.
Edatrexate has also been tested to a certain extent with other various agents in patients with non-small cell lung cancer. For example, positive responses have been reported from the administration of edatrexate with mitomycin and vinblastine (Kris et al., Proc. Am. Soc. Clin. Oncol. 9:229 (1990) and with cisplatin and cyclophosphamide (Lee et al., Cancer 68:959-964 (1991). See, also, Grant et al., supra.
As with other chemotherapeutic drugs, dosages of edatrexate have been limited because of toxic effects of the drug. The primary toxic effect of edatrexate is mucositis, but leukopenia, thrombocytopenia and myelosuppression also occur. Due to side effects, dosages of edatrexate have been, prior to the invention described below, limited to a range of 80 mg/m.sup.2 body surface area/week, with dosages of up to 120 mg/m.sup.2 /week given occasionally. Grant et al., supra, pages 42-44 and Schornagel et al., supra, p. 551. Fatigue, nausea and vomiting are also side effects of the drug, but severity of these events do not appear to correlate with dosage.
Another agent studied for the control of certain cancers is paclitaxel known as TAXOL.RTM.. Paclitaxel was first demonstrated to have activity against refractory ovarian cancer and has subsequently been found to have anti-tumor properties in some breast cancer patients. Seidman, Annals of Oncology 5 (Suppl. 6):S17-S22 (1994). The primary dose limiting toxic effect of paclitaxel is myelosuppression.
As with the multiple chemotherapeutic drugs available, neither edatrexate nor paclitaxel alone is curative for most metastatic breast cancer patients.